NAD⁺ Biology: Metabolism, Sirtuin Regulation, and Cellular Aging

I. Molecular Characteristics and Cellular Distribution

NAD⁺ exists in oxidized (NAD⁺) and reduced (NADH) forms, facilitating vital reversible electron transfer reactions. Synthesis occurs through three primary routes:

• •De novo synthesis: Derived from tryptophan.
• •Preiss–Handler pathway: Synthesized from nicotinic acid.
• •Salvage pathway: Recycled from nicotinamide and nicotinamide riboside.

It is strategically distributed across the cytoplasm, mitochondria, and nucleus to support compartment-specific functions.

II. NAD⁺ & Sirtuin Enzyme Regulation

Sirtuins are NAD⁺-dependent deacetylases that act as metabolic sensors. Their activity is strictly governed by NAD⁺ availability, influencing:

III. Role in Cellular Energy Metabolism

During glycolysis and the TCA cycle, NAD⁺ accepts electrons to become NADH, which then fuels the Mitochondrial Electron Transport Chain for ATP synthesis.

IV. Age-Associated Decline & Pathologies

Intracellular NAD⁺ concentrations naturally decline with age due to decreased biosynthetic capacity and increased consumption by enzymes like PARPs and CD38. This depletion is linked to:

• Neurodegeneration
• Metabolic Syndrome
• Cardiovascular Decay
• Chronic Inflammation

V. Restoring NAD⁺ Homeostasis

Current research emphasizes three primary strategies to replenish NAD⁺ pools:

1. Precursor Supplementation: Utilizing Nicotinamide Riboside (NR) or NMN.
2. Enzymatic Inhibition: Targeting NAD⁺-consuming enzymes (e.g., CD38 inhibitors).
3. Salvage Pathway Activation: Enhancing NAMPT activity.